Paediatric inflammatory multisystem syndrome temporarily associated with SARS‐CoV‐2: It is not over until it's over!

Paediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2: It is not over until it’s over! Rania Haydar ,1,† Andrew M Davis, Bennett Sheridan, Edward Buratto, Georgia Brown and Bryn Jones Department of Pediatric Intensive Care Unit, Royal Children’s Hospital, University of Melbourne, Department of Pediatric Intensive Care Unit, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

1 Cardiac arrhythmia, including advanced atrioventricular block, is being increasingly recognised as a rare complication of paediatric inflammatory multisystem syndrome-temporarily associated with SARS-CoV-2 (PIMS-TS). 1-3 2 Recent cases of arrhythmia highlight the importance of performing a baseline electrocardiogram in all patients presenting with a picture consistent with PIMS-TS regardless of absent cardiac involvement from the outset. This will allow changes to be noted early, permitting rapid anticipation of complications such as arrhythmia and heart block. 3 The medical facility should have the capacity to perform emergent ventricular pacing in severe cases. 4 During the convalescent phase, monitoring of heart rate and oxygen saturation should continue, and symptoms such as syncope require prompt investigations. 5 The WHO clinical management COVID-19 guideline 2021, 4 recommends the use of corticosteroids in addition to supportive care (rather than either IVIG plus supportive care, or supportive care alone). We note that our patient did not receive 'early' steroids. It is worth noting that we do not know if 'early' steroid administration may reduce the risk of cardiac arrhythmia.
1 cannulation (18Fr aortic cannula: dual-stage right atrial venous cannula). High flow ECLS (200 mls/kg) was achieved, consistent with institutional practice for sepsis. 5 Despite achieving high flow ECLS with inotropic support, the aortic valve remained closed with progressive LV dilation, necessitating left atrial (LA) vent insertion. An acute Troponin rise occurred around the time of vent insertion but resolved over the following days. By 72 h of admission, ferritin had peaked, but other inflammatory markers had begun to reduce (Fig. 1). After 105 h of ECLS, an epicardial echocardiogram performed at low ECLS flow again demonstrated normal coronary arteries with improved LV function. Levosimendan was administered in preparation for removal of LA vent and decannulation from ECLS, which occurred on day 6 of admission. 6 Acutely, on day 7 of admission and 1-day post decannulation, our patient developed recurrent episodes of paroxysmal complete AV block (Fig. 2, rhythm strip A). The intermittent reduced output resulted in metabolic acidosis, secondary hyperkalaemia and a lactate rise. Prolonged ventricular pauses were recorded with an intermittent ventricular escape rhythm (Fig. 2, rhythm strip B). Resuscitation included transcutaneous synchronised ventricular pacing until dual-chamber epicardial temporary wires could be sited via redo recent sternotomy, as is institutional preference over transvenous temporary pacing wires. A short run of ventricular tachycardia responded to medical therapy for the secondary hyperkalaemia (Fig. 2, rhythm strip C). Echocardiogram demonstrated good LV posterior wall motion, normal coronary arteries and new valvular involvement with mild mitral regurgitation. Intermittent ventricular pacing using a dual-chamber mode with a long AV interval (250 ms) was required for 36 h until the rhythm spontaneously resolved to first-degree AV block (AV interval < 200 ms), at which time the sternum was closed after cardiac biopsy was performed which demonstrated nonspecific inflammatory changes without evidence of myocarditis and negative SARS-CoV-2 PCR.
By day 11 of admission, our patient was extubated and obeying commands but had profound muscle weakness and remained in first-degree AV block. The ECG done 3 days prior to discharge showed (in addition to a borderline long PR) (Fig. 3), non-specific ST abnormalities including lateral T inversion with minor ST depression. This prompted an echocardiogram to be performed which showed, no pericardial effusion, normal biventricular systolic function and no evidence of coronary ectasia or aneurysm formation. It was therefore judged that the findings were consistent with the non-specific inflammatory changes seen at biopsy and further imaging (such as magnetic resonance imaging) was not required. The patient remained on aspirin at discharge and has since had outpatient follow-up, which demonstrated a PR interval of 160 ms (between 95th and 98th centile for age), 7 normal echocardiogram and a Holter monitor with brief episodes of   3 Wenckebach without higher grade block. Her PR interval was normal during periods of sinus tachycardia. She has no residual deficits and has returned to school. Her most recent outpatient ECG 6 months post-presentation showed a PR interval of 146 ms (Table 1).

Discussion
Coronavirus 2019 (COVID-19), caused by SARS-CoV-2, has been described as temporally associated with a paediatric inflammatory multisystem syndrome (PIMS-TS) also known as multisystem inflammatory syndrome associated with Coronavirus-2019 (MIS-C). 8,9 The WHO case definition for MIS-C/PIMS-TS includes fever, rash, gastrointestinal symptoms and cardiac involvement with elevated markers of inflammation and evidence of COVID-19 infection or exposure. 4 Over 80% of patients with PIMS-TS present along a spectrum of cardiac diseases marked by high concentrations of troponin and brain natriuretic peptide, whereas others develop arrhythmia, left ventricular dysfunction and coronary artery dilatation or aneurysms. 1,9 While the development of conduction system abnormalities is a known complication of coronary ischemia, acute myocarditis and Kawasaki Disease with severe coronary involvement, paroxysmal complete AV block in this patient population is rare and only a recently recognised phenomenon. 2,3 Therefore, other differential diagnoses such as congenital heart disease, drugs, electrolyte imbalances and fibrosis or sclerosis of the conduction system, should be ruled out or treated where appropriate. 10 The mechanism by which COVID-19 can affect the myocardium and conduction system of paediatric patients is not well studied but is suspected to be secondary to inflammation and oedema. Our case adds to an evolving knowledge of MIS-C/PIMS-TS with cardiac features across the spectrum of pancarditis. It appears that most patient groups have a Kawasaki-like presentation with predominant coronary artery involvement, but others may present with conduction system disease and valvar involvement, more consistent with the pancarditis seen in acute rheumatic fever.
Dionne and colleagues reported a similar case of paroxysmal AV block in a PIMS-TS patient with no coronary artery involvement and normal PR interval at presentation. 3 Inflammatory carditis with a risk of advanced AV block would usually demonstrate first-degree AV block at presentation. Our patient had a PR interval of 154 m at presentation, on the 95th centile for age. Thus, it is noteworthy from both Dionne et al. and our case that all children are at risk of paroxysmal AV block in PIMS-TS despite having a normal PR interval at presentation. Serial 12-lead ECG's may be helpful, however may be difficult to perform in dynamic situations and in patients canulated centrally with an open sternum as in our patient. This case also highlights that haemodynamic compromise due to paroxysmal AV block can present in the convalescent stage of this novel hyperinflammatory syndrome.
It is clear from the multiple cases still being reported that there is still much to learn about PIMS-TS and evolving presentations will continue to challenge paediatric physicians world-wide.